Hepatitis C virus (HCV) often causes persistent infection in humans, which may lead to progressive liver disease. We hypothesize that disease progression from chronic HCV infection is attributed, at least in part, to the effect of HCV core protein on the expression of host cellular genes. Our long term goal is to understand the underlying mechanisms behind HCV mediated liver disease progression. We were among the first to identify many intriguing functions related to HCV core protein, which may significantly contribute to disease progression. However, there are critical gaps in our understanding of the key cellular targets and molecular mechanisms by which core protein exerts these functions alone or in context to other HCV proteins. HCV induces hepatocellular insulin resistance and hepatic fibrogenesis. Our focus in this grant application is to examine the underlying mechanisms of HCV induced insulin resistance and fibrogenesis as a follow up to our preliminary data provided with this application. The current research proposal includes complementary but independent aims to address our hypothesis. Aim 1 will investigate the mechanism of IRS phosphorylation by HCV core protein, Aim 2 will investigate the functional correlates of HCV core protein induced metabolic regulators, and Aim 3 will evaluate the role of HCV core protein in hepatic fibrosis. Studies will also be performed using full-length cDNA, replicon or cell culture grown HCV to provide a molecular basis for HCV core protein functions in context to other HCV proteins. Knowledge on the molecular determinants involved in HCV mediated disease progression will open avenues for novel therapeutic approach.